U.S. Pat. No. 5,747,498 disclosed 4-(substituted phenylamino) quinazoline derivatives, processes for their preparation, pharmaceutical compositions in which they are present and method of use thereof. These compounds are Tyrosine Kinase Inhibitors and are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. Among them, erlotinib hydrochloride, chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride is a selective inhibitor of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and is useful for the treatment of proliferative disorders, such as cancers, particularly non small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, head cancer or neck cancer. Erlotinib is represented by the following structure:

Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Erlotinib hydrochloride can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
The U.S. Pat. No. 5,747,498 (herein after referred to as the '498 patent) makes no reference to the existence of specific polymorphic forms of erlotinib hydrochloride. In this patent, it is disclosed that the compound is isolated according to conventional techniques; more precisely, according to the embodiments exemplified, crude erlotinib hydrochloride residue (obtained by reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline with 3-ethynylaniline or its hydrochloride salt in a solvent such as a C1-C6-alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or other aprotic solvents, preferably isopropanol) is basified with saturated aqueous NaHCO3 in the presence of methanol and chloroform followed by flash chromatography on silica using 30% acetone in hexane to afford erlotinib free base, which is further treated with hydrochloric acid in the presence of diethyl ether and chloroform to give erlotinib hydrochloride (melting point: 228°-230° C.).
PCT Patent Publication No. WO 99/55683 disclosed erlotinib mesylate anhydrate and, hydrate polymorphic forms, their method of preparation and pharmaceutical compositions containing thereof.
PCT Patent Publication No. WO 01/34574 A1 (herein after referred to as the '574 patent publication) described two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), characterized by powder X-ray diffraction (p-XRD) pattern. The publication further taught that the synthetic procedure described and exemplified in the '498 patent produces the erlotinib hydrochloride as a mixture of the polymorphs A and B.
According to the '574 patent publication, erlotinib hydrochloride polymorph A is characterized by an X-ray powder diffraction pattern having peaks expressed as 28 at approximately 5.58, 9.84, 11.25, 18.86, 22.70, 23.50, 24.18, 24.59, 25.40 and 29.24 degrees. As per the process exemplified in the '574 patent publication, erlotinib hydrochloride can be obtained in polymorph A form or in a mixture of polymorph A and B, by heating the filtrate containing 3-ethynylaniline in toluene, 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline and acetonitrile to reflux temperature, cooling the reaction mass to between 19 to 25° C. over three to four hours, agitating the reaction mass at a temperature between 20 and 25° C. and isolating erlotinib hydrochloride in polymorph A form or in a mixture of polymorph A and B. The '574 patent publication further taught that the production of the polymorph A is favored by the reduction of the amount of acetonitrile relative to toluene, and particularly favored if isopropanol is used in place of acetonitrile.
According to the '574 patent publication, erlotinib hydrochloride polymorph B is characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at approximately 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and 26.91 degrees. As per process described in the '574 patent publication, the erlotinib hydrochloride polymorph B can be prepared by heating to reflux alcohol, water and the erlotinib hydrochloride so as to form a solution; cooling the solution to between about 65 and 70° C.; clarifying the solution; and precipitating polymorph B by further cooling the clarified solution.
U.S. Patent Application No. 2004/0162300 A1 (herein after referred to as the '300 patent application) mentioned a third polymorphic form of erlotinib hydrochloride, designated as polymorph E, and characterizes it by powder X-ray diffraction, infra-red spectroscopy and by a melting point. According to the '300 patent application, erlotinib hydrochloride polymorph E (characterized by, an X-ray powder diffraction pattern having peaks expressed as 28 at approximately 5.7, 9.7, 10.1, 11.3, 17.0, 17.4, 18.9, 19.6, 21.3, 22.8, 23.6, 24.2, 24.7, 25.4, 26.2, 26.7 and 29.3 degrees, and an IR absorption spectrum having characteristic peaks expressed in cm−1 at approximately 3277, 3057, 16.27, 1070, 1022, 892, 873, 850, 780, 745, 725, and 652 cm−1) can be prepared by reacting 3-ethynylaniline with 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline in (α,α,α)-trifluorotoluene, and precipitating erlotinib hydrochloride polymorph E from the solution of (α,α,α)-trifluorotoluene.
U.S. Patent Application No. 2006/0154941 A1 described an amorphous form of erlotinib hydrochloride prepared by dissolving crystalline erlotinib hydrochloride in an alcoholic solvent to form a solution and removing the solvent from the solution by distillation or spray drying.
The processes described in the prior art produce anhydrous form of erlotinib free base, characterized by, an X-ray powder diffraction pattern having peaks expressed as 28 at about 6.4, 12.8, 15.6, 17.2, 18.2, 19.4, 22.3, 23.4, 23.6, 25.8 and 28.3±0.2 degrees, and the Differential Scanning Calorimetry (DSC) thermogram having a sharp endotherm at 156° C.
We have discovered a novel and stable hydrated crystalline form of erlotinib free base, which differ from the anhydrous form in its stability, in its physical properties, in its spectral characteristics and in its method of preparation. The novel hydrated form is non-hygroscopic, storage stable over the time, obtainable in pure form and can be used to obtain pharmaceutically acceptable salts of erlotinib in high purity.
The erlotinib hydrochloride crystalline polymorph form A obtained by the processes described in the art, for example by the processes described and exemplified in the U.S. Pat. No. 5,747,498 and the PCT Patent Publication No. WO 01/34574 A1, is contaminated with polymorph form B. Specifically, the experimental data disclosed in the '574 patent publication shows that the polymorph A has a peak in PX-RD at about 6.26±0.2 which is the characteristic peak of polymorph B.
Thus, there is a need in the art for a process for producing erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph B.
Extensive laboratory and full-scale research has resulted in a new and inventive crystallization process for producing erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph B which is stable over the time and has good flow properties and is suitable for formulating erlotinib hydrochloride.
The erlotinib hydrochloride product prepared by the methods as described in the prior art has a very small particle size i.e., erlotinib hydrochloride crystalline particles with a mean particle size (D50) ranging from about 2 μm to 3.5 μm and 90 volume-% of the particles (D90) ranging from about 4 μm to 8.5 μm resulting in similarly poor flow properties.
It is well recognized that preparation of tablets with a reproducible composition requires that all the dry ingredients have good flow properties. In cases, where the active ingredient has good flow properties, tablets can be prepared by direct compression of the ingredients. However, in many cases the particle size of the active substance is very small, the active substance is cohesive or has poor flow properties.
Thus, there is a need in the art for erlotinib hydrochloride with a desirable particle size distribution, which has good flow properties, and better dissolution and solubility properties.
Extensive laboratory and full-scale research has resulted in a new and inventive crystallization process for producing erlotinib hydrochloride crystalline particles having mean particle size (D50) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D90) ranging from about 14 μm to 30 μm. Said particles are useful for the manufacture of directly compressed tablets. Accurate dosing in capsules may also be with such particles.
One object of the present invention is to provide a novel and stable hydrated, crystalline form of erlotinib free base and a process for preparing it.
According to another object of the present invention is to provide a novel process for preparing erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph B.
According to another object of the present invention is to provide erlotinib hydrochloride crystalline polymorph form A characterized by peaks in the powder X-ray diffraction pattern having 29 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37±0.2 degrees and by the absence of a peak at about 6.26±0.2 degrees.
According to another object of the present invention is to provide a pharmaceutical composition comprising erlotinib hydrochloride crystalline polymorph form A characterized by peaks in the powder X-ray diffraction pattern having 29 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37±0.2 degrees by the absence of a peak at about 6.26±0.2 degrees.
According to another object of the present invention is to provide erlotinib hydrochloride and formulations containing erlotinib hydrochloride particles having mean particle size (D50) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D90) ranging from about 14 μm to 30 μm, and methods for manufacturing such particles.